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This study was designed to determine whether the National Cholesterol Education Program (NCEP) lipid guidelines accurately identify subclinical atherosclerosis and whether low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels are related to the extent and prematurity of coronary artery disease (CAD) as determined by electron beam tomography (EBT). Out of personal concern for CAD risk, 930 consecutive asymptomatic subjects, without clinical CAD and on no lipid-lowering agents, underwent EBT. Calcium score and percentile were correlated with total cholesterol (TC), LDL-C, HDL-C, triglycerides, and demographic parameters. A calcium score of > 0 (EBT+) was found in 55% of patients; 45% of patients had a 0 score (EBT-). Mean age (58.0 +/- 10.5 vs 49.3 +/- 9.7 years, p = 0.0001), TC (218 +/- 39 vs 211 +/- 41 mg/dl, p = 0.006), LDL-C (136 +/- 36 vs 127 +/- 27 mg/dl, p = 0.005), and TC/HDL-C (4.6 +/- 1.4 vs 4.2 +/- 1.5, p = 0.0001) were significantly higher and HDL-C (52.2 +/- 17.6 vs 55.4 +/- 19.3 mg/dl, p = 0.008) lower in the EBT+ compared with EBT- group. In the EBT+ group, 75.1% of subjects had LDL-C < 160 mg/dl and would not be advised to use lipid-lowering medications according to NCEP guidelines. In subjects with LDL-C < 160 mg/dl, 51.8% of subjects were EBT+, as were 46.1% of those with LDL-C < 100 mg/dl. There were no significant differences in the calcium scores throughout the entire range of all lipid parameters; calcium percentiles were virtually identical within lipid value subgroups. We conclude that asymptomatic patients with EBT-defined subclinical atherosclerosis are not reliably identified by NCEP guidelines, and TC, LDL-C, HDL-C, TC/HDL-C, and triglyceride levels do not correlate with either the extent or prematurity of calcified plaque burden. [ABSTRACT FROM AUTHOR]

We performed a multicenter, open-label study to determine the long-term safety and efficacy of a new extended-release once-a-night niacin preparation, Niaspan, in the treatment of hypercholesterolemia. Niaspan, 0.5 to 3.0 g once a night at bedtime, was used alone or in combination with a statin (inhibitor of hydroxymethylglutaryl coenzyme A reductase), a bile acid sequestrant, or both. Patients included 269 hypercholesterolemic male and female adults enrolled in a 96-week study, and 230 additional adults for whom short-term safety data were available. The dosages of Niaspan attained by 269 patients were 1,000 mg (95% of patients), 1,500 mg (86%), and 2,000 mg (65%). After 48 weeks of treatment, Niaspan alone (median dose 2,000 mg) reduced low-density lipaprotein (LDL) cholesterol (18%), apolipoprotein B (15%), total cholesterol (11%), triglycerides (24%), and lipoprotein(a) (36%), and increased high-density lipoprotein (HDL) cholesterol (29%). Niaspan plus a statin lowered LDL cholesterol (32%), apolipoprotein B (26%), total cholesterol (23%), triglycerides (30%), and lipoprotein(a) (19%), and increased HDL cholesterol (26%). Reversible elevations of aspartate aminotransferase or alanine aminotransferase more than twice the normal range occurred in 2.6% of patients. One patient discontinued Niaspan because of transaminase elevations. Intolerance to flushing, leading to discontinuation of Niaspan, occurred in 4.8% of patients. The overall rate of discontinuance due to flushing in this study combined with 2 previous randomized trials was 7.3%. In the long-term treatment of hypercholesterolemia, Niaspan produced favorable changes in LDL and HDL cholesterol, triglycerides, and lipoprotein(a). Adverse hepatic effects were minor and occurred at rates similar to those reported for statin therapy. [ABSTRACT FROM AUTHOR]

Purpose of Review: Preventive cardiology has an important role to play in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The SARS-CoV-2 pandemic has been observed to have a greater mortality impact on subgroups of people in the population who are deemed to be at higher medical disease risk. Individuals with cardiovascular disorders are one such COVID-19-associated high-mortality risk group., Recent Findings: Evidence is accumulating that COVID-19 infection may worsen an individual's future cardiovascular health, and, preinfection/postinfection cardiovascular evaluation may be warranted to determine if progressive cardiovascular damage has occurred because of COVID-19 infection. In this study, we conducted a systematic review and meta-analysis, focusing on the association between COVID-19 severity and cardiac-specific biomarkers, including N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin T (TnT)/troponin I (TnI), lactate dehydrogenase (LDH), creatine kinase, and creatine kinase isoenzyme (CK-MB). TnT had the highest odds ratio or OR (11.83) indicating the greatest association with COVID-19 severity, followed by NT-proBNP (7.57), TnI (6.32), LDH (4.79), D-dimer (4.10), creatine kinase (3.43), and CK-MB (3.35). All of the biomarkers studied were significantly correlated with COVID-19 severity including severe symptoms, ICU care, and mortality (P < 0.0001, except P < 0.01 for CK-MB)., Summary: COVID-19 infection results in short-term and long-term disease risk that may involve adverse cardiovascular health issues including heart failure. Cardiac-specific biomarkers appear to identify a subset of COVID-19 patients who have the highest risk of an adverse medical outcome. Preventive cardiology has an important role to play in the COVID-19 pandemic.The risk/benefit analysis of maintaining or eliminating the use of the angiotensin receptor blockers (ARB) and angiotensin-converting enzyme inhibitor (ACE-I) medications deserves further investigation., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Non-high-density (HDL)-cholesterol, low-density lipoprotein (LDL)-particle number, apolipoprotein B, lipoprotein(a) (Lp(a)), and small-dense (sdLDL) and large-buoyant (lbLDL) LDL-subfractions are emerging apo B-containing atherosclerotic cardiovascular disease (ASCVD) risk factors. Current guidelines emphasize lifestyle, including weight loss, for ASCVD risk management. Whether weight change affects these emerging risk factors beyond that predicted by traditional triglyceride and LDL-cholesterol measurements remains to be determined., Method: Regression analyses of fasting ∆apo B-containing lipoproteins vs. ∆BMI were examined in a large anonymized clinical laboratory database of 33,165 subjects who did not report use of lipid-lowering medications. Regression slopes (±SE) were estimated as: *∆mmol/L per ∆kg/m 2 , † ∆g/L per ∆kg/m 2 , ‡ ∆% per ∆kg/m 2 , and § ∆μmol/L per ∆kg/m 2 ., Results: When adjusted for age, ∆BMI was significantly related to ∆nonHDL-cholesterol (males: 0.0238 ± 0.0041, P = 7.9 × 10 - 9 ; females: 0.0330 ± 0.0037, P < 10 - 16 )*, ∆LDL-particles (males: 0.0128 ± 0.0024, P = 2.1 × 10 - 7 ; females: 0.0114 ± 0.0022, P = 3.2 × 10 - 7 ) * , ∆apo B (males: 0.0053 ± 0.0010, P = 7.9 × 10 - 8 ; females: 0.0073 ± 0.0009, P = 2.2 × 10 - 16 ) † , ∆sdLDL (males: 0.0125 ± 0.0015, P = 2.2 × 10 - 16 ; females: 0.0128 ± 0.0012, P < 10 - 16 )*, ∆percent LDL carried on small dense particles (%sdLDL, males: 0.296 ± 0.035, P < 10 - 16 ; females: 0.221 ± 0.023, P < 10 - 16 ) ‡ , ∆triglycerides (males: 0.0358 ± 0.0049, P = 2.0 × 10 - 13 ; females: 0.0304 ± 0.0029, P < 10 - 16 )*, and ∆LDL-cholesterol (males: 0.0128 ± 0.0034, P = 0.0002; females: 0.0232 ± 0.0031, P = 1.2 × 10 - 13 )* in both males and females. Age-adjusted ∆BMI was significantly related to ∆lbLDL in females (0.0098 ± 0.0024, P = 3.9 × 10 - 5 )* but not males (0.0007 ± 0.0026, P = 0.78)*. Female showed significantly greater increases in ∆LDL-cholesterol (P = 0.02) and ∆lbLDL (P = 0.008) per ∆BMI than males. ∆BMI had a greater effect on ∆LDL-cholesterol measured directly than indirect estimate of ∆LDL-cholesterol from the Friedewald equation. When sexes were combined and adjusted for age, sex, ∆triglycerides and ∆LDL-cholesterol, ∆BMI retained residual associations with ∆nonHDL-cholesterol (0.0019 ± 0.0009, P = 0.03)*, ∆LDL-particles (0.0032 ± 0.0010, P = 0.001)*, ∆apo B (0.0010 ± 0.0003, P = 0.0008) † , ∆Lp(a) (- 0.0091 ± 0.0021, P = 1.2 × 10 - 5 ) § , ∆sdLDL (0.0001 ± 0.0000, P = 1.6 × 10 - 11 ) * and ∆%sdLDL (0.151 ± 0.018, P < 10 - 16 ) ‡ ., Conclusions: Emerging apo B-containing risk factors show associations with weight change beyond those explained by the more traditional triglyceride and LDL-cholesterol measurements.

Heart attacks kill more Americans than all cancers combined. Fatal heart attack victims have no symptoms until minutes before they die, hence early detection of high-risk asymptomatic individuals is needed. Even though heart attacks kill and cost more than cancers, as a nation we spend over 20 times more on screening for asymptomatic cancer than for asymptomatic atherosclerotic cardiovascular disease (ASCVD), the underlying cause of heart attacks. Currently, payers only cover screening for risk factors of ASCVD such as blood pressure and blood cholesterol. This approach tends to miss high-risk and over-treat low-risk individuals. Although treadmill stress testing with ECG is not indicated for ASCVD detection in asymptomatic individuals, it is done often, and frequently leads to misleading conclusions or unnecessary downstream diagnostic procedures. For example, former President Clinton had passed his treadmill stress tests for several years during his presidential annual checkup but had a heart attack shortly after his presidency. This common practice is a waste of our limited resources. Instead, a more accurate risk assessment using coronary artery calcium (CAC) testing is available; and has just been adopted by ACC/AHA guidelines, however payers do not cover it. CAC is measured non-invasively with a 5-minute CT-scan of the heart, and costs less than $200, whereas cancer screening with colonoscopy and mammography costs over $3000. There is an opportunity to save lives and dollars if CAC testing is covered for appropriately selected individuals. Texas has already passed HB1290 to mandate CAC coverage. Other states must step up and take actions.

Under "treat to risk" goals, low-density (LDL)-cholesterol follow-up measurements monitor statin compliance rather than titration to target levels, however, there is little evidence showing that more-frequent monitoring reduces LDL-cholesterol. We therefore tested whether frequency of blood tests significantly predicted lipoprotein improvements in a large anonymized clinical laboratory database. Differences (∆ ± SE) in total cholesterol, triglycerides, and LDL-cholesterol between baseline and follow-up visits were calculated for 97,548 men and 110,424 women whose physicians sent blood to Boston Heart Diagnostics for analysis between 2010 and 2017. When adjusted for age and follow-up duration, plasma concentration changes per each follow-up measurement in men and women respectively were -2.84 ± 0.10 mg/dL and -3.03 ± 0.10 mg/dL for total cholesterol, -3.78 ± 0.30 mg/dL and -2.26 ± 0.19 mg/dL for triglycerides, and -2.54 ± 0.09 mg/dL and -3.06 ± 0.09 mg/dL for LDL-cholesterol (all P < 10 -16 ). Relative to baseline, significant decreases (P < 10 -16 ) were observed for the 1st, 2nd, and 3rd follow-up measurements for total cholesterol (mean ± SE, men: -9.4 ± 0.1, -11.9 ± 0.2, -13.7 ± 0.3; women: -8.0 ± 0.1, -10.5 ± 0.2, -12.6 ± 0.3 mg/dL, respectively), triglycerides (men: -10.3 ± 0.4, -12.8 ± 0.5, -13.4 ± 0.7; women: -6.4 ± 0.2, -8.8 ± 0.4, -10.1 ± 0.5 mg/dL, respectively) and LDL-cholesterol (men: -7.8 ± 0.1, -9.9 ± 0.2, -11.1 ± 0.2; women: -6.9 ± 0.1, -9.0 ± 0.2, -10.7 ± 0.2 mg/dL, respectively). When adjusted for regression to the mean, 6.9%, 9.9% and 11.8% of men, and 5.7%, 9.7% and 11.5% of women, went from having an LDL-cholesterol ≥160 to <160 mg/dL for their 1st, 2nd, and 3rd follow-up measurements, respectively. We conclude that under usual physician care, total cholesterol, triglyceride, and LDL-cholesterol concentrations decreased progressively with increased physician monitoring within a large patient population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Changes in body mass index (ΔBMI) have well-established relationships to changes in high-density lipoprotein (ΔHDL)-cholesterol concentrations; however, their relationships to ΔHDL subfractions are less well understood., Objective: Assess the associations between ΔHDL and ΔBMI in a very large cohort., Method: Age and sex-adjusted Δapo A1 concentrations were measured within 10 HDL subfractions in 14,121 women and 13,969 men using two-dimensional HDL-mapping. Significance was identified at .01 < P ≤ .05 (*), .001 < P ≤ .01 (†), .0001 < P ≤ .001 (‡), and P ≤ .0001 (§)., Results: ΔBMI was significantly associated with Δα-1 (very large HDL, slope ± SE, females: -0.39 ± 0.07 § ; males: -0.51 ± 0.05 § ), Δα-3 (medium HDL, females: 0.18 ± 0.04 § ; males: 0.19 ± 0.04 § ), and Δα-4 (small HDL, females: 0.14 ± 0.03 § ; males: 0.15 ± 0.04 § mg/dL per kg/m 2 ). As a percent of baseline, the changes in α-1 per ΔBMI were nearly twice as great as the changes in HDL-cholesterol per ΔBMI in both males (-1.53% vs -0.77%) and females (-0.79% vs -0.42%). HDL-cholesterol decreased significantly in healthy-weight patients who became overweight, overweight patients who became class I or class II obese, class I obese patients who became class II obese, and class II obese patients who became class III. In contrast, HDL-cholesterol increased in class III obese patients who became class II or class I, class II obese patients who became class I or overweight, class I patients who became overweight or healthy weight, overweight patients who became healthy weight, and healthy weight patients who became underweight., Conclusions: Weight change significantly affects HDL-cholesterol concentrations throughout the obesity spectrum. ΔBMI's effect on Δα-1 was nearly twice as great as its effect on HDL-cholesterol., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Objective: We tested the hypothesis that a lifestyle program would improve risk factors linked to cardiovascular disease (CVD) in first responders., Methods: A 1-year cluster-randomized controlled clinical trial in 10 cities. Participants were 175 first responders, with increased waist circumference and/or low levels of large (α1) high-density lipoprotein (HDL) particles. The intervention group received personalized online tools and access to telephonic coaching sessions., Results: At 1 year the intervention significantly reduced body weight (P = 0.004) and waist circumference (P = 0.002), increased α1 HDL (P = 0.01), and decreased triglyceride (P = 0.005) and insulin concentrations (P = 0.03). Program adherence was associated with weight loss (P = 0.0005) and increases in α1 HDL (P = 0.03)., Conclusions: In first responders, a personalized lifestyle intervention significantly improved CVD risk factors in proportion to program adherence. Changes in large HDL particles were more sensitive indicators of lifestyle changes than HDL-cholesterol measurement., Clinical Trial Registration Number: ClinicalTrials.gov: NCT03322046.

Background: Over a 14-year period, age-adjusted high total cholesterol (≥240 mg/dL) in the United States declined from 18.3% in 1999 to 2000 to 11.0% in 2013 to 2014, coinciding with the 2001 National Cholesterol Education Program Adult Treatment Panel (ATP)-III guidelines that endorsed low-density lipoprotein (LDL)-cholesterol blood value goals. Statin treatment recommendations were revised by the American College of Cardiology and the American Heart Association (ACC/AHA) in November 2013 to a "risk-based prescription" approach that did not utilize blood cholesterol values. This increased dosage and expanded the statin-eligible population by an estimated 12.8 million US adults. These changes should further lower total and LDL cholesterol concentrations nationally., Methods: We examined data from 507 752 patients nationally aged ≥16 years whose fasting bloods were sent to Boston Heart Diagnostics for direct LDL-cholesterol measurements. Between 2012 and 2017, age-adjusted concentrations were examined by analysis of covariance and LDL-cholesterol ≥160 mg/dL by logistic regression., Results: Contrary to expectations, age-adjusted mean LDL-cholesterol concentrations (±SE, mg/dL) increased significantly (P < 10 -16 ) in men (2012:113.8 ± 0.3; 2013:115.3 ± 0.2; 2014:114.7 ± 0.2; 2015:116.0 ± 0.2; 2016:117.6 ± 0.2; and 2017:117.1 ± 0.2 mg/dL) and women (2012:119.5 ± 0.3; 2013:120.7 ± 0.2; 2014:119.8 ± 0.02; 2015:120.8 ± 0.2; 2016:122.7 ± 0.1; and 2017:123.8 ± 0.2 mg/dL). The percentage with LDL-cholesterol ≥160 mg/dL also increased significantly (P < 10 -9 ) in men and women. Similar results were obtained for ages 40 to 75 years olds (corresponding to ACC/AHA guidelines)., Conclusion: These results provide additional evidence that declining blood LDL-cholesterol levels observed following the ATP-III recommendations, did not further decline (actually increased) following the 2013 ACC/AHA recommendations., (© 2018 Wiley Periodicals, Inc.)

Niacin (nicotinic acid) has been used for primary and secondary coronary heart disease prevention for over 40 years. Until recently clinical trials incorporating niacin as part of an intervention strategy consistently demonstrated reduction in clinical events and lesion improvement, including ≥6% absolute mortality reduction. Two large clinical event trials in 2011 (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) and 2014 (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) concluded that niacin added to statin therapy did not provide clinical event benefit over statin alone. This has prompted some individuals to call for an end to the use of niacin in statin-treated patients and the US Food and Drug Administration to halt marketing of statin/niacin combination tablets. There are significant differences between the earlier clinical trials that revealed cardiovascular benefit of niacin and the 2 trials that failed to demonstrate a benefit. These differences include dyslipidemia types, niacin formulation, dosing, and timing. In general, the patient population that benefits the most from incorporating niacin in their treatment regimen can be defined by elevations in low-density lipoprotein cholesterol and triglycerides, and reduced high-density lipoprotein cholesterol. The niacin formulation and dose should be capable of achieving adequate lipoprotein change. Mealtime dosing of niacin, as opposed to bedtime dosing, may avoid a counter-regulatory hormone response, including catecholamines, because of altered fuel supply potentially leading to unexpected cardiovascular outcomes., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Context: Patients with nonalcoholic fatty liver disease (NAFLD) are at increased risk of cardiovascular disease, and atherogenic lipoproteins may play an important role., Objective: The objective of the study was to determine the contribution of the severity of steatohepatitis to atherogenic dyslipidemia in patients with NAFLD., Design: This was a cross-sectional study., Setting: The study was conducted at a university hospital., Patients: Patients were recruited from outpatient clinics or from the general population (n = 188)., Interventions: Measurement of hepatic triglyceride content by magnetic resonance spectroscopy, histology (liver biopsy), metabolic profile by means of an oral glucose tolerance test, and lipoprotein analyses were performed., Outcomes: Outcomes measured included standard lipids, lipoprotein subfraction analysis (apolipoprotein B/A1 levels, low-density lipoprotein (LDL) particle size/phenotype, and LDL/high-density lipoprotein subfractions), and insulin resistance., Results: Patients with NAFLD had severe insulin resistance, especially at the level of the adipose tissue, when compared with patients without NAFLD. Despite small differences in triglycerides and high-density lipoprotein-cholesterol, patients with NAFLD had a significantly higher plasma apolipoprotein B to apolipoprotein A1 ratio (0.66 ± 0.02 vs 0.58 ± 0.02, P = .01) and smaller LDL particle size (216.2 ± 0.7 vs 219.4 ± 1.1 Å, P = .01). Of note, these differences between patients with/without NAFLD were independent of the presence of obesity. Severity of steatohepatitis did not significantly influence the lipoprotein profile. Worse atherogenic dyslipidemia was best predicted by the degree of liver fat accumulation and adipose tissue and systemic insulin resistance., Conclusions: NAFLD was associated with a worse atherogenic lipoprotein profile, regardless of similar body mass index and other clinical parameters. We speculate that this lipoprotein profile is driven mostly by liver fat content and insulin resistance and appears not to be worsened by obesity or the severity of liver disease (nonalcoholic steatohepatitis).

Background: Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo., Methods and Results: In 11 186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility-measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88-1.21). In contrast, associations with CVD events were observed for baseline non-high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01-1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11-1.48), and ion mobility-measured non-HDL particles (HR, 1.19; 95% CI, 1.05-1.35) and LDL particles (HR, 1.21; 95% CI, 1.07-1.37). Association with CVD events was also observed for several LDL and very-low-density lipoprotein subfractions but not for ion mobility-measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-C, non-HDL cholesterol, and apolipoprotein B; these were also associated with CVD/all-cause death, as were several LDL and very-low-density lipoprotein subfractions, albeit with a pattern of association that differed from the baseline risk., Conclusions: In JUPITER, baseline LDL-C was not associated with CVD events, in contrast with significant associations for non-HDL cholesterol and atherogenic particles: apolipoprotein B and ion mobility-measured non-HDL particles, LDL particles, and select subfractions of very-low-density lipoprotein particles and LDL particles. During high-intensity statin therapy, on-treatment levels of LDL-C and atherogenic particles were associated with residual risk of CVD/all-cause death., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681., (© 2015 American Heart Association, Inc.)

Statin-related myopathy (SRM) undermines drug adherence that is critical for achieving the benefits of lipid-lowering therapy. While the exact mechanism of SRM remains largely unknown, recent evidence supports specific genetic and immunologic influence on the development of intolerance. Genes of interest include those involved in the pharmacokinetics of statin response (i.e. drug metabolism, uptake transporters, and efflux transporters), pharmacodynamics (i.e. drug toxicity and immune-mediated myopathy), and gene expression. We examine the influence of genetic and immunologic variation on the pharmacokinetics, pharmacodynamics, and gene expression of SRM., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Despite the clinical benefit of statin therapy and the numerous strategies used to improve adherence, no strategy has used direct communication of genetic test results to the patient as an adherence and persistence motivator. We investigated in a real-world setting the effect of a process of providing KIF6 test results and risk information directly to 647 tested patients on 6-month statin adherence (proportion of days covered (PDC)) and persistence compared with concurrent non-tested matched controls. Adjusted 6-month statin PDC was significantly greater in tested patients: 0.77 (95% confidence interval (CI) 0.72-0.82) vs controls 0.68 (95% CI 0.63-0.73), P<0.0001. Significantly more tested patients were adherent (PDC⩾0.80) (63.4% (59.6-67.1%) vs 45.0% (41.1-48.8%), P<0.0001) and persisted on therapy (69.1% (65.4-72.5%) vs 53.3% (49.4-57.1%), P<0.0001). Similar results were observed in a secondary comparison with 779 unmatched patients who declined testing. The Additional KIF6 Risk Offers Better Adherence to Statins trial provides the first evidence that pharmacogenetic testing may modify patient adherence.

Pharmacogenetics uses the genetic variation in metabolic pathways to identify groups of patients who may respond differently in terms of therapeutic and adverse effects. Much clinical interest lies in drug metabolism and the opportunity to improve prescribing efficacy and safety. Owing to widespread use and increasing concern regarding side effects, statins are of significant interest in this area. Among other benefits, statins have been shown to improve lipid profiles and reduce coronary heart disease event rates in many populations. However, variability in drug response exists, and genetic variability may be a contributing factor. Our primary goal is to feature the most important genes involved in lipid metabolism, clinical outcomes, and statin-induced side effects, highlighting genome-wide association studies and the candidate gene approach.

Background: Low-density lipoprotein cholesterol (LDL-C) lowering is the primary objective of patient management for cardiovascular disease. However, large numbers of patients who have achieved their LDL-C goal remain at risk for cardiovascular events. Low-density lipoprotein subfractions may provide insight into this residual risk. Thus, LDL subfraction standardization and consistency are critical to these efforts., Aim: This study aimed to determine the agreement of the analytical results among 4 methods commonly used for LDL subfractionation, namely, segmented gradient gel electrophoresis (sGGE), ultracentrifugation-vertical auto profile (VAP), nuclear magnetic resonance (NMR), and ion mobility (IM)., Methods: Blood samples were collected from 228 apparently healthy adults and sent to 4 clinical reference laboratories for analysis. The LDL phenotype was reported as pattern A (larger, less dense particles) or pattern B (smaller, more dense particles), respectively, and was the primary measure of comparison. An intermediate pattern (A/B) was also reported for sGGE and VAP., Results: We observed complete agreement in the LDL phenotype among the 4 methods in 64% of subjects and agreement among at least 3 of the 4 methods in 87% of subjects. Agreement among pairs of methods ranged from 73% to 98% depending on how differences in reporting of subjects with intermediate results were considered. When subjects having intermediate A/B pattern were excluded, sGGE and IM had the highest agreement (98%) of any pair of methods., Conclusions: We found substantial agreement in the reported LDL phenotype among 4 LDL subfraction measurement technologies as performed by different clinical reference laboratories.

Objectives: We report annual trends in low density lipoprotein cholesterol (LDL-C) from an in-care patient population of nearly 105 million adults across the United States (U.S.), from 2001 through 2011., Background: Average blood cholesterol values have declined in the U.S. since at least 1960. The National Health and Nutrition Examination Survey (NHANES) reported declining blood cholesterol values from 1999 through 2010. In the absence of more recent published data, we examined LDL-C values from a single clinical laboratory database to determine whether these values continued to decline through 2011., Methods and Results: We extracted almost 247 million LDL-C results from nearly 105 million adults who received diagnostic testing from a single national clinical laboratory. Annual age-adjusted mean LDL-C values were calculated, and analyzed by gender. Piecewise regression analysis of the total study population indicates a breakpoint, or change in slope, in the years following 2008 (F = 163.13; p<0.05). Between 2001 and 2008, the average rate of annual decline was -2.05 mg/dL (95% CI [-2.35, -1.75]). After 2008, mean LDL-C levels flattened out, with a slope not statistically different from zero (slope = -0.10 mg/dL/year; 95% CI [-1.46, 1.26]). This stabilization was observed in both genders and all age ranges, and was also reflected in the percentage of results in low- and high-risk categories., Conclusions: The trends reported suggest historical progress in decreasing LDL-C levels, observed from 2001-2008, may have stalled in recent years. Further research is needed to determine the cause of the observed trends and develop new strategies to reduce lipid-based cardiovascular risk further.

Objective: To assess the clinical utility of measuring high-density lipoprotein (HDL) subfractions to assess coronary heart disease (CHD) risk., Methods: Literature review of 80 published investigations., Results: Measurements of HDL2b by gradient gel electrophoresis provided more consistent evidence of CHD risk than measurement of HDL2 cholesterol. Five of the seven studies that compared the extent or progression of atherosclerosis with gradient gel electrophoresis estimates of HDL subclasses (71%) assigned statistical significance to HDL2b. Ten of the 11 case-control comparisons (91%) reported lower HDL2b in cases. In contrast, of the 16 association studies relating HDL2 cholesterol and HDL3 cholesterol to extent of disease, five reported no significant relationships with either subfraction, two reported significant relationships with both HDL2 and HDL3 cholesterol, four reported significant relationships with HDL2 but not HDL3 cholesterol, and five reported relationships with HDL3 but not HDL2 cholesterol. Forty-five percent of the case-control comparisons reported that both HDL2 cholesterol and HDL3 cholesterol were significantly lower in cases than controls, 17% failed to find significance for either subfraction, and the remainder reported significantly lower values in cases for HDL2 cholesterol only (26%) or HDL3 cholesterol only (11%). On average, the case-control differences were similar for HDL2 (-0.12 ± 0.01 mmol/L) and HDL3 cholesterol (-0.10 ± 0.02 mmol/L), although relative to controls, the percent reduction was twice as great for HDL2 (-25.7 ± 2.9%) than HDL3 cholesterol (-12.1 ± 1.5%). Eight prospective studies were identified and four reported that both HDL2 and HDL3 predicted lower risk for CHD, one reported reductions in risk for HDL2 but not HDL3 cholesterol, and three reported reductions in risk for HDL3 but not HDL2 cholesterol. None of the prospective studies show that measurements of HDL cholesterol subfractions improve the identification of persons at risk., Conclusions: HDL2 and HDL3 cholesterol do not distinguish cardioprotective differences between HDL subclasses. More extensive characterization of HDL particles by one or two dimensional gel electrophoresis, ion mobility, or ultracentrifugation may provide more specific information about CHD risk than the measurement of HDL cholesterol, HDL3 cholesterol, or HDL2 cholesterol., (Copyright © 2012 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor medications, commonly referred to as statins, are among the most widely prescribed medications. Variation in individual response to statins concerning low-density lipoprotein cholesterol reduction, clinical event benefit, and side effects has been observed. Some of this variability is attributed to demographic and environmental issues, chief of which is compliance. A large portion of the individual response to statin therapy is attributed to single nucleotide polymorphisms that have recently been elucidated, several of which seem to have clinical utility., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Coronary heart disease (CHD) often presents suddenly with little warning. Traditional risk factors are inadequate to identify the asymptomatic high-risk individuals. Early identification of patients with subclinical coronary artery disease using noninvasive imaging modalities would allow the early adoption of aggressive preventative interventions. Currently, it is impractical to screen the entire population with noninvasive coronary imaging tools. The use of relatively simple and inexpensive genetic markers of increased CHD risk can identify a population subgroup in which benefit of atherosclerotic imaging modalities would be increased despite nominal cost and radiation exposure. Additionally, genetic markers are fixed and need only be measured once in a patient's lifetime, can help guide therapy selection, and may be of utility in family counseling.

Objective: To determine the association of cardiovascular risk markers with noninvasive imaging of atherosclerosis in firefighters., Methods: Cross-sectional investigation of subclinical atherosclerosis with metabolic, work related, and life-style variables in 296 professional firefighters., Results: Calcified coronary atherosclerosis (CAC), carotid arterial intimal thickness (CIMT), and electrocardiogram provided independent CVD assessments. Homeostatic Model Assessment (HOMA) concentrations were related to heart-rate-corrected QT (QTc) (slope ± SE: 2.16 ± 65, P = 0.001), average common CIMT (0.019 ± 0.005 mm, P = 0.0005), and total CAC lesions (0.269 ± 0.116, P = 0.02). Stepwise linear regression selected fasting insulin as the strongest predictor for QTc, HOMA as the strongest predictor of average CIMT, and fasting glucose as the strongest predictor of total coronary lesion number and score., Conclusion: Firemen's HOMA and fasting insulin and glucose concentrations were significantly associated with three measures of CVD. Aspects of insulin resistance are related to CVD risk among firefighters.

A family history of coronary heart disease (CHD) is an accepted risk factor for cardiovascular events and is independent of common CHD risk factors. Advances in the understanding of genetic influences on CHD risk provide the opportunity to apply this knowledge and improve patient care. Utility of inherited cardiovascular risk testing exists by utilizing both phenotypes and genotypes and includes improved CHD risk prediction, selection of the most appropriate treatment, prediction of outcome, and family counseling. The major impediment to widespread clinical adoption of this concept involves un-reimbursed staff time, educational needs, access to a standardized and efficient assessment mechanism, and privacy issues. The link between CHD and inheritance is indisputable and the evidence strong and consistent. For clinicians, the question is how to utilize this information, in an efficient manner, in order to improve patient care and detection of high-risk family members., (Copyright © 2010 Wiley Periodicals, Inc.)

Objective: To compare the effects of combination niacin extended-release + simvastatin (NER/S) versus atorvastatin alone on apolipoproteins and lipid fractions in a post hoc analysis from SUPREME, a study which compared the lipid effects of niacin extended-release + simvastatin and atorvastatin in patients with hyperlipidemia or mixed dyslipidemia., Patients and Methods: Patients (n = 137) with dyslipidemia (not previously receiving statin therapy or having discontinued any lipid-altering treatment 4-5 weeks prior to the study) received NER/S (1000/40 mg/day for four weeks, then 2000/40 mg/day for eight weeks) or atorvastatin 40 mg/day for 12 weeks. Median percent changes in apolipoprotein (apo) A-1, apo B, and the apo B:A-I ratio, and nuclear magnetic resonance lipoprotein subclasses from baseline to week 12 were compared using the Wilcoxon rank-sum test and Fisher's exact test., Results: NER/S treatment produced significantly greater percent changes in apo A-I and apo B:A-I, and, at the final visit, apo B < 80 mg/dL was attained by 59% versus 33% of patients, compared with atorvastatin treatment (P = 0.003). NER/S treatment resulted in greater percent reductions in calculated particle numbers for low-density lipoprotein (LDL, 52% versus 43%; P = 0.022), small LDL (55% versus 45%; P = 0.011), very low-density lipoprotein (VLDL) and total chylomicrons (63% versus 39%; P < 0.001), and greater increases in particle size for LDL (2.7% versus 1.0%; P = 0.007) and VLDL (9.3% versus 0.1%; P < 0.001), compared with atorvastatin., Conclusion: NER/S treatment significantly improved apo A-I levels and the apo B:A-I ratio, significantly lowered the number of atherogenic LDL particles and VLDL and chylomicron particles, and increased the mean size of LDL and VLDL particles, compared with atorvastatin.

Evidence from multiple large prospective studies suggests that a common polymorphism that encodes an arginine (Arg)-to-tryptophan substitution at position 719 in the KIF6 gene is associated with coronary heart disease (CHD) and reduction in coronary events from statin therapy. Carriers of the 719Arg allele were at greater risk for primary and secondary CHD events, and statin therapy significantly reduced coronary events in 719Arg carriers but not in noncarriers. The number needed to treat to prevent a single CHD event ranged from 10 to 20 for 719Arg carriers, compared to >80 for noncarriers in the Cholesterol and Recurrent Events (CARE) study, the West of Scotland Coronary Prevention Study (WOSCOPS), the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) study. In conclusion, assessment of 719Arg carrier status holds promise for stratification of coronary event risk and for selection of optimal therapy in primary and secondary CHD prevention., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: CAC has been used to predict obstructive CAD on invasive coronary angiography. However, it is unknown how the prevalence of obstructive CAD in patients with zero CAC is influenced by the presence or absence of chest pain., Methods: 210 consecutive patients referred for CAC and CorCTA were included in this analysis. Chest pain was defined based on the Diamond-Forrester classification., Results: 134 patients (64%) were symptomatic and 76 (36%) were asymptomatic. Seventy patients had negative (33%); 140 had positive CAC (67%). In the symptomatic group with zero CAC, 8.2% (4/49) had an obstructive, non-calcified plaque; of these, 3 were <45 years. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CAC in the symptomatic population for detection of obstructive CAD were 0.86 (0.66-0.95), 0.42 (0.33-0.52), 0.28 (0.19-0.39) and 0.92 (0.8-0.97), respectively (p=0.007). No asymptomatic subject with zero CAC had obstructive CAD. Sensitivity, specificity, PPV and NPV of CAC in the asymptomatic population for detection of obstructive CAD were 1.00 (0.66-1.00), 0.32 (0.21-0.45), 0.18 (0.10-0.31) and 1.00 (0.80-1.00), respectively (p=0.05). Optimal cut-points to predict obstructive CAD and AUC were significantly different in symptomatic versus asymptomatic subjects (91 and 0.78 vs. 296 and 0.89, respectively) (p=0.005). CAC performed much better in symptomatic patients >45 years compared to younger patients to exclude obstructive CAD (AUC: 0.83 vs. 0.5, p<0.001; NPV=0.98)., Conclusions: CAC is better in asymptomatic compared to symptomatic subjects, especially in patients

The goal of this study was to determine, using analytic ultracentrifugation, the effect of nicotinic acid alone or nicotinic acid added to gemfibrozil on lipoprotein subclass distribution, including intermediate-density lipoprotein (IDL; low-density to very low density flotation rate [S(f)] 12 to 20); low-density lipoprotein (LDL) subfractions LDL-I (S(f) 7 to 12), LDL-II (S(f) 5 to 7), LDL-III (S(f) 3 to 5), and LDL-IV (S(f) 0 to 3); and high-density lipoprotein (HDL) subfractions HDL(2) (high-density flotation rate 3.5 to 9.0) and HDL(3) (high-density flotation rate 0 to 3.5). Patients with combined hyperlipidemia were randomized to nicotinic acid (1,500 mg/day) plus placebo or nicotinic acid plus gemfibrozil (1,200 mg/d) for 12 weeks. Baseline characteristics were similar between the 2 groups, and mean LDL cholesterol (180 +/- 33 mg/dl) and triglycerides (310 +/- 126 mg/dl) were typical for patients with combined hyperlipidemia. Treatment with nicotinic acid resulted in a reduction in dense LDL (S(f) 5 to 7; p = 0.02), which was counterbalanced by an increase in buoyant LDL (S(f) 7 to 12; p = 0.03) that resulted in no significant LDL mass or LDL cholesterol change. IDL was reduced (p = 0.005) and HDL(2) increased by 143% (p = 0.004). The combination of nicotinic acid and gemfibrozil resulted in a further 17.8% reduction in apolipoprotein B (p = 0.06), a further 33.8% reduction in IDL (p = 0.06), and a greater reduction in the apolipoprotein B/apolipoprotein A-I ratio (p = 0.02). The combination of nicotinic acid and gemfibrozil reduced atherogenic by IDL 71%, dense LDL-III by 52%, and apolipoprotein B by 37% and increased protective HDL(2) by 90%. In conclusion, this investigation revealed that a combination of a fibric acid derivative and nicotinic acid offers greater improvement in detailed lipoprotein subclass distribution and apolipoprotein ratios than monotherapy.

The role of low-density lipoprotein cholesterol (LDL-C) in the pathogenesis of cardiovascular disease (CVD) and the clinical benefit of lowering LDL-C in high-risk patients is well established. What remains controversial is whether we are using the best measure(s) of LDL characteristics to identify all individuals who are at CVD risk or if they would benefit from specific therapies. Despite the successful LDL-C reduction trials, substantial numbers of patients continue to have clinical events in the treatment groups. The size of LDL particles and assessment of the number of LDL particles (LDL-Num) have been suggested as a more reliable method of atherogenicity. Each LDL particle has one apoprotein B-100 measure attached; therefore, determination of whole plasma apoprotein B can be considered the best measure of LDL-Num. Because the cholesterol content per LDL particle exhibits large interindividual variation, the information provided by LDL-C and LDL-Num is not equivalent. Individuals with the same level of LDL-C may have higher or lower numbers of LDL particles and, as a result, may differ in terms of absolute CVD risk. LDL particle size and number provide independent measures of atherogenicity and are strong predictors of CVD.

We tested the hypothesis that gemfibrozil has a differential effect on low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclass distributions and postprandial lipemia that is different in subjects classified as having LDL subclass pattern A or LDL pattern B who do not have a classic lipid disorder. Forty-three normolipemic subjects were randomized to gemfibrozil (1,200 mg/day) or placebo for 12 weeks. Lipids and lipoproteins were determined by enzymatic methods. The mass concentrations of lipoproteins in plasma were determined by analytic ultracentrifugation and included the S(f) intervals: 20 to 400 (very LDL), 12 to 20 (intermediate-density lipoprotein), 0 to 12 (LDL), and HDL(2) mass (F(1.20) 3.5 to 9.0) and HDL(3) mass (F(1.20) 0 to 3.5). Postprandial measurements of triglycerides and lipoprotein(a) were taken after the patients consumed a 500 kcal/M(2) test meal. Treatment with gemfibrozil, compared with placebo, significantly reduced fasting plasma triglycerides (difference from placebo +/- SE; -50.2 +/- 20.6 mg/dl, p = 0.02), total cholesterol (-16.4 +/- 7.5 mg/dl, p = 0.04), apolipoprotein B (-16.1 +/- 5.5 mg/dl, p = 0.006), very LDL mass of S(f) 20 to 400 (-50.8 +/- 24.1 mg/dl, p = 0.02), S(f) 20 to 60 (-17.5 +/- 8.5 mg/dl, p = 0.05), S(f) 60 to 100 (-16.2 +/- 8.1 mg/dl, p = 0.05), and increased peak S(F) (0.48 +/- 0.27 Svedberg, p = 0.08). Gemfibrozil reduced the postprandial triglyceride level significantly at 3 (p = 0.04) and 4 (p = 0.05) hours after the test meal. A significantly different subclass response to gemfibrozil was observed in those with LDL pattern A versus B. Those with LDL pattern B had a significantly greater reduction in the small LDL mass S(f) 0 to 7 (p = 0.04), specifically regions S(f) 0 to 3 (p = 0.009) and S(f) 3 to 5 (p = 0.009). In conclusion, normolipemic subjects with either predominantly dense or buoyant LDL respond differently to gemfibrozil as determined by the changes in LDL subclass distribution. Thus, treatment with gemfibrozil may have additional antiatherogenic effects in those with LDL pattern B by decreasing small dense LDL that is not apparent in those with pattern A.

Individuals of Asian Indian descent have significantly higher cardiovascular event rates as compared with other ethnic groups. The authors investigated the prevalence of metabolic disorders linked to coronary artery disease in an Asian Indian male population compared with non-Asian Indian males. Standard lipid measurements did not discriminate between groups, and the Asian Indian group exhibited less of the high coronary artery disease risk small low-density lipoprotein trait. Despite less of the small low-density lipoprotein trait in the Asian Indian group and no difference in high-density lipoprotein cholesterol, the Asian Indian group had a significantly higher prevalence (p < 0.0002) of low high-density lipoprotein 2b, implying impaired reverse cholesterol transport. This observation remained significant in the subgroup of patients with high-density lipoprotein cholesterol over 40 mg/dL, a region felt not to reflect impaired reverse cholesterol transport. Low high-density lipoprotein 2b combined with the higher lipoprotein(a) in the Asian Indian group may help explain the high prevalence of coronary artery disease in this ethnic population.

Coronary atherosclerosis is the result of multiple complex metabolic disorders acting alone or in combination. Metabolic cardiology has advanced considerably in the past decade and now offers cardiologists a sophisticated approach to treating the underlying cause(s) of coronary artery disease in patients seen in invasive cardiology practices. Disorders which have now been powerfully linked to coronary artery disease include the small low-density lipoprotein trait, impaired reverse cholesterol transport, homocysteinemia, insulin resistance, aspects of inflammation, and infectious burden. These disorders are common and alone, or in combination, are found in over 90% of patients with coronary artery disease. Treatments for these disorders are well elucidated and have been associated with cardiovascular benefit. Incorporation of a sophisticated metabolic atherosclerosis management unit into existing invasive cardiology practices offers the cardiologist and patient many benefits. The cardiologist obtains a powerful tool that complements invasive cardiology, provides patients with access to cutting-edge diagnosis and treatment, and provides a forum that allows incorporation of clinically valid advances in metabolic cardiovascular care in a time frame far shorter than the traditional consensus recommendation approach. Incorporation of such a clinical service is consistent with the recent American College of Cardiology focus on the "CardioTeam."